In asymptomatic patients with chronic severe aortic regurgitation (AR), the timing of valve replacement (AVR) is routinely determined by serial evaluation of resting left ventricular (LV) size and function. However, early signs of myocardial dysfunction may not be detected with currently used methods. The purpose of this study was to investigate whether the myocardial response to inotropic stimulation at the initial evaluation is related to progressive LV dilation, LV dysfunction, or the development of symptoms during follow-up which would, in turn, prompt the recommendation for AVR. To this end, we studied 28 patients (23 men and 5 women; age 45+/-14 years) with chronic severe AR who, at the time of entry into the study, were asymptomatic, did not have severe LV dilation (LV end-diastolic [LVD]/ end-systolic [LVS] dimensions < 75/55 mm), and had normal LV function (resting ejection fraction [EF] > 45%). Upon entry into the study, patients underwent echocardiography during incremental infusion of dobutamine from 5 to 20 mcg/kg/min. At each stage, systolic thickening (ST) was measured in the short-axis view at the papillary muscle level using the centerwall method. Serial routine echocardiograms, radionuclide ventriculograms, and exercise testing were performed every 6-12 months to determine the need for AVR, irrespective of the results of the initial dobutamine echocardiogram. After a mean follow-up of 71 months (range 34 to 90), 18 patients (Group 1) remained asymptomatic without progressive LV dilation or dysfunction. Of the remaining 10 patients (Group 2), 9 required AVR and 1 patient died, an average of 40 months (range 1 to 83) after the dobutamine echocardiogram (attrition rate 6% per year). At initial evaluation, there were no significant differences in resting LVD, LVS, EF or exercise tolerance (ET) between the two groups; however, patients in Group 2 had significantly depressed response to inotropic stimulation with dobutamine: LVD(mm) 64+/-6 vs 67+/-6 (p=0.16); LVS(mm) 40+/-7 vs 44+/-6 (p=0.12); EF(%) 58+/-9 vs 56+/-10 (p=0.51); ET(min) 14.2+/-4.0 vs 11.9+/-6.6 (p=0.33); ST with dobutamine(mm) 7.1+/-1.2 vs 5.3+/-0.9 (p= 0.003) (Group 1 vs Group 2, respectively, for all comparisons. Hence, in asymptomatic patients with chronic severe AR, a diminished contractile reserve is associated with development of symptoms, progressive LV dilation or dysfunction during follow-up. Assessment of the myocardial response to inotropic stimulation may therefore unmask early signs of myocardial dysfunction and thus aid in the serial evaluation of these patients.